rs730881500

Positions:

• chr17-43045769-G-A
• chr17-43045769-G-C
• chr17-43045769-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BP6

The NM_007294.4(BRCA1):​c.5501C>T​(p.Thr1834Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2 O:1
• Conservation: PhyloP100: 2.07

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a strand (size 2) in uniprot entity BRCA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41632992).
• BP6: Variant 17-43045769-G-A is Benign according to our data. Variant chr17-43045769-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182171.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5501C>T	p.Thr1834Ile	missense_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5501C>T	p.Thr1834Ile	missense_variant	23/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251252 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 27, 2022	This missense variant replaces threonine with isoleucine at codon 1834 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study found that this variant has a neutral effect in a haploid cell proliferation assay (PMID: 30219179). This variant has been reported in an individual affected with breast cancer (PMID: 24356096). This variant has been identified in 2/251252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 01, 2024	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, criteria provided, single submitter	curation	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 12, 2024	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh38:17:43045769:G>A was assigned evidence codes ['BS3'] and an overall classification of Likely benign -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2023	Published functional studies demonstrate no damaging effect: classified as functional based on a cell survival assay (Findlay et al., 2018); Observed in individuals undergoing multi-gene panel testing due to a personal and/or family history of cancer (Li et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5620C>T; This variant is associated with the following publications: (PMID: 30209399, 31853058, 27742776, 24356096, 25348405, 29884841, 32377563) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 29, 2024	The BRCA1 c.5501C>T (p.Thr1834Ile) variant has been reported in the published literature in an individual undergoing multigene panel testing (PMID: 31853058 (2020)). This variant has also been reported as a somatic variant in an individual with triple negative breast cancer (PMID: 24356096 (2014)). One study showed this variant apparently retained functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). The frequency of this variant in the general population, 0.000008 (2/251252 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2023

Variant summary: BRCA1 c.5501C>T (p.Thr1834Ile) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251252 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5501C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group (Tavtigian_2018). Five (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1834 of the BRCA1 protein (p.Thr1834Ile). This variant is present in population databases (rs730881500, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182171). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;T;T;T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D;N;.;.;.;.;N;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.017	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		0.77, 0.97	.;P;.;.;.;D;.;.
Vest4		0.26
MVP		0.93
MPC		0.44
ClinPred		0.72	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730881500; hg19: chr17-41197786; COSMIC: COSV104621700;